Project 2: Genetics of aging and longevity related traits in the domesticated dog Abstract Benjamin Franklin famously remarked, ?In this world nothing can be said to be certain, except death and taxes?, and decades of research have led to remarkable progress in understanding the genetic and environmental determinants of longevity. Nonetheless, considerable gaps in knowledge remain about how and why individuals differ in aging and longevity related phenotypes, largely due to the complex interaction of variables that influence the quantity and quality of life. The domesticated dog is an ideal model organism to investigate the genetic architecture of aging and longevity related phenotypes given its simplified genetic background and shared environmental exposures with humans. The goal of this project is to leverage state of the art genomics, statistical, and computational tools to systematically probe the genetic architecture of aging and longevity related traits in 10,000 dogs. Specifically, in Aim 1 we will develop powerful genomics resources by performing whole-genome sequencing on 35 carefully selected dogs, and use this and existing genome- scale data, to supplement existing high-density SNP genotyping chips. We will genotype all 10,000 dogs for approximately 235,000 SNPs throughout the canine genome. These data will facilitate all downstream analyses in this project, as well as analyses in other projects as part of the U19. In Aim 2, we will comprehensively investigate the genetic architecture of longevity and disease related traits segregating in the panel of 10,000 dogs. In particular, we will perform genome-wide association studies (GWAS) of common diseases, cellular and immune related traits, and measures of frailty developed in Project 1. Importantly, we will take advantage of the unique and powerful collection of environmental covariates collected by the Environment Core D that will improve power for genetic mapping and enable detection of gene x environment interactions. Finally, in Aim 3 we will investigate the genetic architecture of centenarian dogs (defined as individuals in the top 1% of breed specific age distributions). To this end, we will perform GWAS with common variants and targeted resequencing of 500 aging-related genes to test the hypothesis that rare and common variants in these genes influence exceptional lifespan. Collectively, these data will profoundly increase our understanding on the genetic determinants of aging and longevity related traits and how these factors interact with the environment. Moreover, our data will be a considerable resource to the scientific community, and we will make all project data easily accessible.